New Genetic Variants of RUNX2 in Mexican Families Cause Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia characterized by persistent open skull sutures with bulging calvaria, hypoplasia, or aplasia of clavicles permitting abnormal opposition of the shoulders; wide public symphysis; short middle phalanx of the fifth fingers; and vertebral, craniofacial, and dental anomalies. It is a rare disease, with a prevalence of 1-9/1,000,000, high penetrance, and variable expression. The gene responsible for CCD is the Runt-related transcription factor 2 (RUNX2) gene. We characterize the clinical, genetic, and bioinformatic results of four CCD cases: two cases within Mexican families with six affected members, nine asymptomatic individuals, and two sporadic cases with CCD, with one hundred healthy controls. Genomic DNA analyses of the RUNX2 gene were performed for Sanger sequencing. Bioinformatics tools were used to predict the function, stability, and structural changes of the mutated RUNX2 proteins. Three novel heterozygous mutations (c.651_652delTA; c.538_539delinsCA; c.662T>A) and a previously reported mutation (c.674G>A) were detected. In silico analysis showed that all mutations had functional, stability-related, and structural alterations in the RUNX2 protein. Our results show novel mutations that enrich the pool of RUNX2 gene mutations with CCD. Moreover, the proband 1 presented clinical data not previously reported that could represent an expanded phenotype of severe expression.

DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol. / [Artículo traducido] Genotipado del gen DPYD y toxicidad de las 5-fluoropirimidinas: protocolo de un resumen de revisiones sistemáticas.

INTRODUCTION: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in dihydropyridine dehydrogenase deficient patients. The main objective of this overview is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity. METHODS AND ANALYSIS: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment and data collection. Discrepancies will be solved by a third investigator.

DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol.

INTRODUCTION: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase (DPD) deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in DPD deficient patients. The main objective of this overview of systematic reviews is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity. METHODS AND ANALYSIS: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus, and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment, and data collection. Discrepancies will be solved by a third investigator. REGISTRATION DETAILS: Registration number in PROSPERO: CRD42023401226.

Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America: an analysis within the ESTAMPA study.

Background: Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30-64 years participating in the ESTAMPA study. Methods: Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated. Findings: 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0-53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3-96.7). Specificity was 96.5% (95% CI: 96.3-96.7) using cytology and 88.7% (95% CI: 88.3-89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%-100% and 83.6-90.8%, respectively). Interpretation: The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America. Funding: IARC/WHO, UNDP, HRP/WHO, NCI and local funders.

Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases.

BACKGROUND: The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized. METHODS: We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases. RESULTS: We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation. CONCLUSIONS: Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.

First reported double drug-drug interaction in a cancer renal patient under everolimus treatment: therapeutic drug monitoring and review of literature.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) used in both transplantation and cancer treatment (breast, renal and neuroendocrine). In transplantation, therapeutic drug monitoring (TDM) is recommended due to the potential drug-drug interactions with chronic medications, which can affect everolimus pharmacokinetics. In cancer treatment, everolimus is used at higher doses than in transplantation and without a systematic drug monitoring.We present a case report of a 72-year-old woman with epilepsy history to whom everolimus 10 mg QD was prescribed as third line of treatment for renal cell carcinoma (RCC). The potential drug interactions between everolimus and the patient's chronic medications, carbamazepine and phenytoin, are significant as both are known as strong inducers CYP3A4 metabolism, potentially leading to underexposure to everolimus.TDM of everolimus was recommended by the pharmacist. The literature suggests that a minimum plasma concentration (Cminss) of everolimus over 10 ng/ml is associated with better response to treatment and progression-free survival (PFS). The patient's everolimus dose had to be increased until 10 mg BID, and regular monitoring of everolimus levels showed an increase in Cminss from 3.7 ng/ml to 10.8 ng/ml.This case highlights the importance of checking for potential drug interactions and monitoring everolimus levels in patients on chronic medication, especially those with several inducers or inhibitors of CYP3A4 metabolism. TDM can help to ensure that patients are treated with their optimal dose, which can improve the effectiveness of the treatment or minimize the risk of toxicities.

Efecto del tratamiento de la morfología oclusal con materiales para restauraciones preventivas / Effect of treating occlusal morphology with materials for preventive restorations

Introducción: las fosas y fisuras son áreas formadas por delgadas irregularidades de la capa del esmalte de la superficie oclusal. La compleja morfología en dientes posteriores es un determinante biológico asociado al desarrollo de caries. Objetivo: evaluar el efecto de diversas formas de tratar la morfología oclusal en la adaptación y penetración de materiales utilizados en restauraciones preventivas. Material y métodos: diseño experimental e in vitro. Sesenta terceros molares fueron distribuidos aleatoriamente en dos grupos: surco sin ameloplastia y con ameloplastia; además, contaban con acondicionamiento del esmalte que se subdividió en tres subgrupos: 1) sellador de fosas y fisuras, 2) adhesivo/sellador de fosas y fisuras y 3) adhesivo/ resina Flow. Resultados: los subgrupos adhesivo/sellador y adhesivo/ Flow alcanzaron mayores valores de adaptación íntima a las paredes del surco. Las diferencias fueron significativas entre los materiales (p = 0.0009). Las mayores zonas de desadaptación resultaron para el sellador sin y con ameloplastia. La penetración de los materiales fue mayor en los surcos con ameloplastia. En los surcos tratados con ameloplastia, el adhesivo/Flow reveló el mayor porcentaje de penetración y la mejor adaptación a las paredes del surco. Conclusiones: la penetración del material está positivamente correlacionada con la profundidad del surco. El sellador con y sin ameloplastia mostró pobre adaptación a las paredes del surco (AU)

Introduction: pits and fissures are areas formed by fine irregularities in the enamel layer of the occlusal surface. The complex morphology in posterior teeth are biological determinants associated with the development of caries. Objective: to evaluate the effect of various ways of treating occlusal morphology on the adaptation and penetration of materials used in preventive restorations. Material and methods: experimental design, in vitro. Sixty third molars were randomly distributed into two groups: groove without ameloplasty and with ameloplasty, with enamel conditioning with three subgroups: 1) pit and fissure sealer, 2) adhesive/pit and fissure sealer, 3) adhesive/resin flow. Results: the adhesive/sealant and adhesive/flow subgroups reached higher values of intimate adaptation to the furrow walls. The differences were significant between the materials (p = 0.0009). The largest areas of maladjustment were found for the sealant without and with ameloplasty. The penetration of the materials was greater in the grooves with ameloplasty. In the grooves treated with ameloplasty, the adhesive/flow revealed the highest percentage of penetration and the best adaptation to the walls of the groove. Conclusions: the penetration of the material is positively correlated with the depth of the furrow. The sealant with and without ameloplasty showed poor adaptation to the sulcus walls (AU)

Choreiform movements and basal ganglia calcification as a presentation of Fahr's disease

Basal ganglia calcifications may be a radiological finding in approximately 20% of the general population. When they are associated with neuropsychiatric and motor symptoms in an idiopathic form, they are known as Fahr's disease. They are termed "Fahr's syndrome" when they are secondary to an identifiable and potentially treatable cause. In this report, we present the clinical case of a 69-year-old woman with the onset of subacute chorea, with no other associated symptoms, in whom extensive basal ganglia calcifications were found on neuroimaging, due to which metabolic disorders were subsequently ruled out. The objective is to contribute to the characterization of the potential motor manifestations which would give rise to clinical suspicion. Due to its low incidence and the little information on this condition in the region, we want to encourage documentation of other cases and the process for ruling out other differential diagnoses, in order to obtain more information on its actual epidemiology and signs and symptoms in Colombia. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2635).

Performance of standardised colposcopy to detect cervical precancer and cancer for triage of women testing positive for human papillomavirus: results from the ESTAMPA multicentric screening study.

BACKGROUND: Colposcopy, currently included in WHO recommendations as an option to triage human papillomavirus (HPV)-positive women, remains as the reference standard to guide both biopsy for confirmation of cervical precancer and cancer and treatment approaches. We aim to evaluate the performance of colposcopy to detect cervical precancer and cancer for triage in HPV-positive women. METHODS: This cross-sectional, multicentric screening study was conducted at 12 centres (including primary and secondary care centres, hospitals, laboratories, and universities) in Latin America (Argentina, Bolivia, Colombia, Costa Rica, Honduras, Mexico, Paraguay, Peru, and Uruguay). Eligible women were aged 30-64 years, sexually active, did not have a history of cervical cancer or treatment for cervical precancer or a hysterectomy, and were not planning to move outside of the study area. Women were screened with HPV DNA testing and cytology. HPV-positive women were referred to colposcopy using a standardised protocol, including biopsy collection of observed lesions, endocervical sampling for transformation zone (TZ) type 3, and treatment as needed. Women with initial normal colposcopy or no high-grade cervical lesions on histology (less than cervical intraepithelial neoplasia [CIN] grade 2) were recalled after 18 months for another HPV test to complete disease ascertainment; HPV-positive women were referred for a second colposcopy with biopsy and treatment as needed. Diagnostic accuracy of colposcopy was assessed by considering a positive test result when the colposcopic impression at the initial colposcopy was positive minor, positive major, or suspected cancer, and was considered negative otherwise. The main study outcome was histologically confirmed CIN3+ (defined as grade 3 or worse) detected at the initial visit or 18-month visit. FINDINGS: Between Dec 12, 2012, and Dec 3, 2021, 42 502 women were recruited, and 5985 (14·1%) tested positive for HPV. 4499 participants with complete disease ascertainment and follow-up were included in the analysis, with a median age of 40·6 years (IQR 34·7-49·9). CIN3+ was detected in 669 (14·9%) of 4499 women at the initial visit or 18-month visit (3530 [78·5%] negative or CIN1, 300 [6·7%] CIN2, 616 [13·7%] CIN3, and 53 [1·2%] cancers). Sensitivity was 91·2% (95% CI 88·9-93·2) for CIN3+, whereas specificity was 50·1% (48·5-51·8) for less than CIN2 and 47·1% (45·5-48·7) for less than CIN3. Sensitivity for CIN3+ significantly decreased in older women (93·5% [95% CI 91·3-95·3] in those aged 30-49 years vs 77·6% [68·6-85·0] in those aged 50-65 years; p<0·0001), whereas specificity for less than CIN2 significantly increased (45·7% [43·8-47·6] vs 61·8% [58·7-64·8]; p<0·0001). Sensitivity for CIN3+ was also significantly lower in women with negative cytology than in those with abnormal cytology (p<0·0001). INTERPRETATION: Colposcopy is accurate for CIN3+ detection in HPV-positive women. These results reflect ESTAMPA efforts in an 18-month follow-up strategy to maximise disease detection with an internationally validated clinical management protocol and regular training, including quality improvement practices. We showed that colposcopy can be optimised with proper standardisation to be used as triage in HPV-positive women. FUNDING: WHO; Pan American Health Organization; Union for International Cancer Control; National Cancer Institute (NCI); NCI Center for Global Health; National Agency for the Promotion of Research, Technological Development, and Innovation; NCI of Argentina and Colombia; Caja Costarricense de Seguro Social; National Council for Science and Technology of Paraguay; International Agency for Research on Cancer; and all local collaborative institutions.

Performance of visual inspection of the cervix with acetic acid (VIA) for triage of HPV screen-positive women: results from the ESTAMPA study.

VIA is recommended for triage of HPV-positive women attending cervical screening. In the multicentric ESTAMPA study, VIA performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV-positive women was evaluated. Women aged 30-64 years were screened with HPV testing and cytology and referred to colposcopy if either test was positive. At colposcopy visit, study-trained midwives/nurses/GPs performed VIA ahead of colposcopy. VIA was considered positive if acetowhite lesions were observed in or close to the transformation zone. Ablative treatment eligibility was assessed for VIA positives. Performance indicators were estimated. Three thousand one hundred and forty-two HPV-positive women were included. Sensitivity for CIN3+ was 85.9% (95% CI 81.2-89.5) among women <50 years and, although not significant, slightly lower in women 50+ (78.0%, 95% CI 65.9-86.6). Overall specificity was 58.6% (95% CI 56.7-60.5) and was significantly higher among women 50+ (70.3%, 95% CI 66.8-73.5) compared to women <50 (54.3%, 95% CI 52.1-56.5). VIA positivity was lower among women 50+ (35.2%, 95% CI 31.9-38.6) compared to women <50 (53.2, 95% CI 51.1-55.2). Overall eligibility for ablative treatment was 74.5% and did not differ by age. VIA sensitivity, specificity, and positivity, and ablative treatment eligibility varied highly by provider (ranges: 25%-95.4%, 44.9%-94.4%, 8.2%-65.3%, 0%-98.7%, respectively). VIA sensitivity for cervical precancer detection among HPV-positive women performed by trained providers was high with an important reduction in referral rates. However, scaling-up HPV screening triaged by VIA will be challenging due to the high variability of VIA performance and providers' need for training and supervision.

Cardiac amyloidosis and left atrial appendage closure. The CAMYLAAC study.

INTRODUCTION AND OBJECTIVES: Transthyretin cardiac amyloidosis (ATTR-CA) patients often have atrial fibrillation and increased bleeding/thrombogenic risks. We aimed to evaluate outcomes of left atrial appendage closure (LAAC) compared with patients without a known diagnosis of CA. METHODS: Comparison at long-term of patients diagnosed with ATTR-CA who underwent LAAC between 2009 and 2020 and those without a known diagnosis of CA. RESULTS: We studied a total of 1159 patients. Forty patients (3.5%) were diagnosed with ATTR-CA; these patients were older and had more comorbidities, higher HAS-BLED and CHA2DS2-VASc scores, and lower left ventricular function. Successful LAAC was achieved in 1137 patients (98.1%) with no differences between groups. Regarding in-hospital and follow-up complications, there were no differences between the groups in ischemic stroke (5% vs 2.5% in those without a known diagnosis of CA; P=.283), hemorrhagic stroke (2.5% and 0.8% in the control group; P=.284), major or minor bleeding. At the 2-year follow-up, there were no significant differences in mortality (ATTR-CA: 20% vs those without known CA: 13.6%, 0.248); however, the at 5-year follow-up, ATTR-CA patients had higher mortality (40% vs 19.2%; P <.001) but this difference was unrelated to hemorrhagic complications or ischemic stroke. CONCLUSIONS: LAAC could reduce the risk of bleeding complications and ischemic cerebrovascular events without increasing the rate of early or mid-term complications. Although long-term survival was impaired in ATTR-CA patients, it was comparable to that of patients without a known diagnosis of CA at the 2-year follow-up, suggesting that LAAC for patients with ATTR-CA might not be futile.

Concordancia de los hallazgos citológicos, colposcópicos e histológicos en lesiones premalignas del cuello uterino / Concordance in cytological, colposcopic and histological findings in premalignant lesions of the cervix

Resumen OBJETIVO: Determinar la concordancia de los hallazgos citológicos, colposcópicos e histopatológicos en lesiones premalignas del cuello uterino. MATERIALES Y MÉTODOS: Estudio transversal, retrospectivo y comparativo, efectuado en la Clínica de Displasias del Hospital General Regional 1 del estado de Querétaro, México, del 1 de enero a diciembre del 2020, con base en la información de los expedientes de mujeres con reporte citológico, colposcópico e histopatológico (biopsia) de lesión intraepitelial de bajo y alto grado. El plan de análisis estadístico incluyó intervalos de confianza para promedios y porcentajes. Se utilizó el Índice de Kappa ponderado para conocer el nivel de concordancia. RESULTADOS: Se analizaron 290 expedientes. La edad promedio de las pacientes fue 36 años, el índice de kappa ponderado fue k = 0.41 (IC95%: 0.33-0.53) para la citología y la colposcopia con un valor moderado (regular). Para la citología y la biopsia fue de k= 0.33 (IC95%: 0.22-0.49) con un valor escaso (medio). En cuanto a la colposcopia y la biopsia fue de k = 0.61 (IC95%: 0.49-0.72) con un valor de buena (sustancial) concordancia. CONCLUSIÓN: Entre la citología y la colposcopia el coeficiente de concordancia fue moderado, para la citología y la biopsia fue escaso, mientras que para la colposcopia y la biopsia fue un sustancial.

Abstract OBJECTIVE: To determine the concordance in cytologic, colposcopic and histopathologic findings in premalignant lesions of the uterine cervix. MATERIALS AND METHODS: Cross-sectional, retrospective and comparative study, carried out in the dysplasia clinic of the Hospital General Regional 1 of the state of Querétaro, Mexico, from January 1 to December 2020, based on information from the records of women with cytology, colposcopy and histopathology (biopsy) report with low- and high-grade intraepithelial lesion. The statistical analysis plan included confidence intervals for averages and percentages. The weighted Kappa Index was used to determine the level of concordance. RESULTS: Two hundred and ninety records were analyzed. The mean age of the patients was 36 years, the weighted kappa index was k = 0.41 (95%CI: 0.33-0.53) for cytology and colposcopy with a moderate value (fair). For cytology and biopsy, it was k= 0.33 (95%CI: 0.22-0.49) with a poor value (medium). For colposcopy and biopsy, it was k = 0.61 (95%CI: 0.49-0.72) with a value of good (substantial) agreement. CONCLUSION: Between cytology and colposcopy the concordance coefficient was moderate, for cytology and biopsy it was poor, while for colposcopy and biopsy it was a substantial.

Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance.

While great strides have been made in the treatment of advanced renal cell carcinoma (RCC) with the emergence of immune checkpoint inhibitors (ICIs) and VEGFR-targeting drugs, sizable proportions of patients still do not respond to upfront therapy and long-term responses only occur in a minority of patients. There is therefore a great need for the development of better predictors of response and an increased understanding of mechanisms of resistance to these therapies. Alternative immune checkpoints outside the PD-1/PD-L1 axis, such as LAG3, have been implicated as one mechanism of resistance to ICIs. These checkpoints thus represent attractive therapeutic targets, and indeed the LAG3 inhibitor relatlimab was recently approved for the treatment of metastatic melanoma in combination with anti-PD-1 therapy. LAG3 inhibitors are being evaluated for RCC as well. In this context, a better understanding of LAG3 expression patterns in RCC and how they relate to clinicopathologic features of disease and response to immunotherapy may give insight into mechanisms of resistance to PD-1 inhibitors and aid in the identification of subgroups of patients more likely to benefit from certain drug regimens. In this study, we assessed LAG3 protein levels in leukocytes in normal kidney adjacent to RCC, primary RCC tumors, and matched metastatic tumors, including large numbers of brain metastases. We found that LAG3 protein levels are on average lower at metastatic sites compared to matched primary tumors, and that the difference was more pronounced in patients with high-risk clinical characteristics, including those with larger primary tumor size, grade 4 tumors, IMDC poor-risk disease, and initial presentation with brain metastases. We further saw that the prognostic value of LAG3 levels varies depending on the tissue site queried (i.e., primary tumor versus metastases), and that relatively higher LAG3 levels at metastatic sites may predict a better response to immunotherapy and longer overall survival after the development of metastatic disease. These findings may have important implications for the design of future studies involving LAG3 or other immunotherapies in RCC.

Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury: State of the Art and Perspectives.

Diagnosis of cardiac surgery-associated acute kidney injury (CSA-AKI), a syndrome of sudden renal dysfunction occurring in the immediate post-operative period, is still sub-optimal. Standard CSA-AKI diagnosis is performed according to the international criteria for AKI diagnosis, afflicted with insufficient sensitivity, specificity, and prognostic capacity. In this article, we describe the limitations of current diagnostic procedures and of the so-called injury biomarkers and analyze new strategies under development for a conceptually enhanced diagnosis of CSA-AKI. Specifically, early pathophysiological diagnosis and patient stratification based on the underlying mechanisms of disease are presented as ongoing developments. This new approach should be underpinned by process-specific biomarkers including, but not limited to, glomerular filtration rate (GFR) to other functions of renal excretion causing GFR-independent hydro-electrolytic and acid-based disorders. In addition, biomarker-based strategies for the assessment of AKI evolution and prognosis are also discussed. Finally, special focus is devoted to the novel concept of pre-emptive diagnosis of acquired risk of AKI, a premorbid condition of renal frailty providing interesting prophylactic opportunities to prevent disease through diagnosis-guided personalized patient handling. Indeed, a new strategy of risk assessment complementing the traditional scores based on the computing of risk factors is advanced. The new strategy pinpoints the assessment of the status of the primary mechanisms of renal function regulation on which the impact of risk factors converges, namely renal hemodynamics and tubular competence, to generate a composite and personalized estimation of individual risk.

Infección por COVID-19 en pacientes oncológicos y asociación con el tratamiento recibido / COVID-19 infection in cancer patients and association with the antineoplastic treatment

Resumen La evidencia que relaciona la terapia oncológica con la incidencia por COVID-19 varía según el tipo de terapia administrada. La incidencia informada en pacientes que reciben tratamiento oncológico varía entre 1 y 4%. El objetivo del presente estudio fue determinar la incidencia por COVID-19 en pacientes oncológicos en tratamiento activo y evaluar si existe asociación con el esquema recibido. Se utilizó una cohorte retrospectiva que incluyó de forma consecutiva a los pacientes adultos que realizaron tratamiento ambulatorio desde marzo/2020 hasta abril/2021 en un Hospital Público de referencia. El evento principal fue el diagnóstico confirmado de COVID-19. La asociación con los tratamientos oncológicos fue evaluada mediante regresión logís tica multivariada ajustando por edad, sexo, localización del tumor, cobertura de salud y localidad de residencia. Se incluyeron 463 pacientes, mediana de edad 58 años (RIC = 47-66), 73.3% (n = 337) mujeres. La incidencia de COVID-19 fue 5.6% (n = 26) con una tasa de mortalidad del 12% (n = 3). El riesgo de infección fue mayor en los que estaban realizando tratamiento únicamente con anticuerpos monoclonales, 14.3% vs. 4.9% (OR-ajustado = 3.3, p = 0.03) y aquellos en tratamiento con inhibidores de puntos de control inmunológicos, 23.1% vs. 5.1% (OR-ajustado = 5.8, p = 0.03). La quimioterapia citotóxica, sola o en combinación con anticuerpos mo noclonales, no presentó mayor riesgo de infección. La edad, sexo, sitio tumoral, cobertura de salud y localidad de residencia no se asoció con la incidencia de COVID-19. En base a nuestros resultados, el tratamiento con anticuerpos monoclonales o inhibidores de puntos de control inmunológicos se asoció con mayor incidencia de infección por COVID-19.

Abstract Evidence linking anticancer therapy with the incidence of COVID-19 varies according to the type of therapy administered. The reported COVID-19 incidence in patients receiving antineoplastic treatment varies between 1 and 4%. The aim of this study was to determine the incidence of COVID-19 in cancer patients under active treatment and to assess whether there is an association with the received anticancer therapy. It was a retrospective cohort that consecutively included adult outpatients who underwent treatment in a referral center from March 2020 to April 2021. The primary endpoint was the confirmed diagnosis of COVID-19. The association with anticancer treatments was evaluated using multivariate logistic regression adjusting for age, sex, tumor site, health coverage status, and place of residence. The sample included 463 patients, the median age was 58 years (IQR = 47-66), 73.3% (n = 337) were women. The incidence of COVID-19 was 5.6% (n = 26) with a mortality rate of 12% (n = 3). The risk of infection was higher in patients undergoing treatment only with monoclonal antibod ies, 14.3% vs. 4.9% (adjusted OR = 3.3, p = 0.03) and those in treatment with immunotherapy, 23.1% vs. 5.1% (adjusted OR = 5.8, p = 0.03). Cytotoxic chemotherapy, alone or in combination with monoclonal antibodies, did not present an increased risk of infection. Age, sex, tumor site, health coverage, and place of residence did not show association with the incidence of COVID-19. Based on our results, treatment with monoclonal antibodies or immunotherapy was associated with a higher rate of COVID-19 infection while chemotherapy did not modify the incidence of COVID-19.

Distribution of human papillomavirus genotypes by severity of cervical lesions in HPV screened positive women from the ESTAMPA study in Latin America.

The proportion of HPV16 and 18-associated cervical cancer (CC) appears rather constant worldwide (≥70%), but the relative importance of the other HR-HPV differs slightly by geographical region. Here, we studied the HPV genotype distribution of HPV positive Latin American (LA) women by histological grade, in a sub-cohort from the ESTAMPA study; we also explored the association of age-specific HPV genotypes in severe lesions. Cervical samples from 1,252 participants (854 ≤CIN1, 121 CIN2, 194 CIN3 and 83 CC) were genotyped by two PCRs-Reverse Blotting Hybridization strategies: i) Broad-Spectrum General Primers 5+/6+ and ii) PGMY9/11 PCRs. HPV16 was the most frequently found genotype in all histological grades, and increased with the severity of lesions from 14.5% in ≤ CIN1, 19.8% in CIN2, 51.5% in CIN3 to 65.1% in CC (p < 0.001). For the remaining HR-HPVs their frequency in CC did not increase when compared to less severe categories. The nonavalent vaccine HR-types ranked at the top in CC, the dominant ones being HPV16 and HPV45. HR-HPV single infection occurs, respectively, in 57.1% and 57.0% of ≤CIN1 and CIN2, increasing to 72.2% and 91.6% in CIN3 and CC (p<0.001). No association between age and HPV type was observed in CC, although the risk of HPV16 infection in CIN3 cases increased with age. Results confirm the relevance of HPV16 in the whole clinical spectrum, with a strong rise of its proportion in CIN3 and cancer. This information will be relevant in evaluating the impact of HPV vaccination, as a baseline against which to compare genotype changes in HPV type-specific distribution as vaccinated women participate in screening in LA region. Likewise, these data may help select the best HPV testing system for HPV-based efficient, affordable, and sustainable screening programmes.

DNA-Binding Properties of Bis-N-substituted Tetrandrine Derivatives.

A series of bis-N-substituted tetrandrine derivatives carrying different aromatic substituents attached to both nitrogen atoms of the natural alkaloid were studied with double-stranded model DNAs (dsDNAs) to examine the binding properties and mechanism. Variable-temperature molecular recognition studies using UV-vis and fluorescence techniques revealed the thermodynamic parameters, ΔH, ΔS, and ΔG, showing that the tetrandrine derivatives exhibit high affinity toward dsDNA (K ≈ 105-107 M-1), particularly the bis(methyl)anthraquinone (BAqT) and bis(ethyl)indole compounds (BInT). Viscometry experiments, ethidium displacement assays, and molecular modeling studies enabled elucidation of the possible binding mode, indicating that the compounds exhibit a synergic interaction mode involving intercalation of one of the N-aryl substituents and interaction of the molecular skeleton in the major groove of the dsDNA. Cytotoxicity tests of the derivatives with tumor and nontumor cell lines demonstrated low cytotoxicity of these compounds, with the exception of the bis(methyl)pyrene (BPyrT) derivative, which is significantly more cytotoxic than the remaining derivatives, with IC50 values against the LS-180, A-549, and ARPE-19 cell lines that are similar to natural tetrandrine. Finally, complementary electrochemical characterization studies unveiled good electrochemical stability of the compounds.

The Protective Role of pVHL in Imiquimod-Induced Psoriasis-like Skin Inflammation.

Psoriasis is a chronic inflammatory disease distinguished by an excessive proliferation and abnormal differentiation of keratinocytes. Immune cells, such as T lymphocytes and neutrophils, and inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and interleukin 17 (IL-17), are essential for maintaining psoriatic lesions. Additionally, a hypoxic milieu present in the skin promotes the expression of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α). This protein regulates the expression of angiogenic and glycolytic factors, such as vascular endothelial grown factor and lactate dehydrogenase (LDH), both relevant in chronic inflammation. The von Hippel-Lindau protein (pVHL) is a negative regulator of HIF-1α. Previously, we found that pVHL was almost absent in the lesions of psoriasis patients; therefore, we investigated the impact of rescue pVHL expression in lesional skin. We used the imiquimod-induced psoriasis-like mouse model as an adenoviral vector that allowed us to express pVHL in the skin. Our data show that, in lesional skin, pVHL expression was reduced, whereas HIF-1α was increased. Remarkably, the retrieval of pVHL prevented psoriatic lesions, diminishing erythema, scale, and epidermal and vascular thickness. Furthermore, pVHL expression was capable of reducing HIF-1α, LDH, TNF-α and immune cell infiltration (mainly IL-17+ neutrophils). In conclusion, our results demonstrate that pVHL has a protective role to play in the pathophysiology of psoriasis.

[COVID-19 infection in cancer patients and association with the antineoplastic treatment]. / Infección por COVID-19 en pacientes oncológicos y asociación con el tratamiento recibido.

Evidence linking anticancer therapy with the incidence of COVID-19 varies according to the type of therapy administered. The reported COVID-19 incidence in patients receiving antineoplastic treatment varies between 1 and 4%. The aim of this study was to determine the incidence of COVID-19 in cancer patients under active treatment and to assess whether there is an association with the received anticancer therapy. It was a retrospective cohort that consecutively included adult outpatients who underwent treatment in a referral center from March 2020 to April 2021. The primary endpoint was the confirmed diagnosis of COVID-19. The association with anticancer treatments was evaluated using multivariate logistic regression adjusting for age, sex, tumor site, health coverage status, and place of residence. The sample included 463 patients, the median age was 58 years (IQR = 47-66), 73.3% (n = 337) were women. The incidence of COVID-19 was 5.6% (n = 26) with a mortality rate of 12% (n = 3). The risk of infection was higher in patients undergoing treatment only with monoclonal antibodies, 14.3% vs. 4.9% (adjusted OR = 3.3, p = 0.03) and those in treatment with immunotherapy, 23.1% vs. 5.1% (adjusted OR = 5.8, p = 0.03). Cytotoxic chemotherapy, alone or in combination with monoclonal antibodies, did not present an increased risk of infection. Age, sex, tumor site, health coverage, and place of residence did not show association with the incidence of COVID-19. Based on our results, treatment with monoclonal antibodies or immunotherapy was associated with a higher rate of COVID-19 infection while chemotherapy did not modify the incidence of COVID-19.

La evidencia que relaciona la terapia oncológica con la incidencia por COVID-19 varía según el tipo de terapia administrada. La incidencia informada en pacientes que reciben tratamiento oncológico varía entre 1 y 4%. El objetivo del presente estudio fue determinar la incidencia por COVID-19 en pacientes oncológicos en tratamiento activo y evaluar si existe asociación con el esquema recibido. Se utilizó una cohorte retrospectiva que incluyó de forma consecutiva a los pacientes adultos que realizaron tratamiento ambulatorio desde marzo/2020 hasta abril/2021 en un Hospital Público de referencia. El evento principal fue el diagnóstico confirmado de COVID-19. La asociación con los tratamientos oncológicos fue evaluada mediante regresión logística multivariada ajustando por edad, sexo, localización del tumor, cobertura de salud y localidad de residencia. Se incluyeron 463 pacientes, mediana de edad 58 años (RIC = 47-66), 73.3% (n = 337) mujeres. La incidencia de COVID-19 fue 5.6% (n = 26) con una tasa de mortalidad del 12% (n = 3). El riesgo de infección fue mayor en los que estaban realizando tratamiento únicamente con anticuerpos monoclonales, 14.3% vs. 4.9% (ORajustado = 3.3, p = 0.03) y aquellos en tratamiento con inhibidores de puntos de control inmunológicos, 23.1% vs. 5.1% (OR-ajustado = 5.8, p = 0.03). La quimioterapia citotóxica, sola o en combinación con anticuerpos monoclonales, no presentó mayor riesgo de infección. La edad, sexo, sitio tumoral, cobertura de salud y localidad de residencia no se asoció con la incidencia de COVID-19. En base a nuestros resultados, el tratamiento con anticuerpos monoclonales o inhibidores de puntos de control inmunológicos se asoció con mayor incidencia de infección por COVID-19.

6-Month Outcomes of the TricValve System in Patients With Tricuspid Regurgitation: The TRICUS EURO Study.

BACKGROUND: Severe tricuspid regurgitation (TR) is frequently associated with significant morbidity and mortality; such patients are often deemed to be at high surgical risk. Heterotopic bicaval stenting is an emerging, attractive transcatheter solution for these patients. OBJECTIVES: The aim of this study was to evaluate the 30-day safety and 6-month efficacy outcomes of specifically designed bioprosthetic valves for the superior and inferior vena cava. METHODS: TRICUS EURO (Safety and Efficacy of the TricValve® Transcatheter Bicaval Valves System in the Superior and Inferior Vena Cava in Patients With Severe Tricuspid Regurgitation) is a nonblinded, nonrandomized, single-arm, multicenter, prospective trial that enrolled patients from 12 European centers between December 2019 and February 2021. High-risk individuals with severe symptomatic TR despite optimal medical therapy were included. The primary endpoint was quality-of-life (QOL) improvement measured by Kansas City Cardiomyopathy Questionnaire score and New York Heart Association (NYHA) functional class improvement at 6-month follow-up. RESULTS: Thirty-five patients (mean age 76 ± 6.8 years, 83% women) were treated using the TricValve system. All patients at baseline were in NYHA functional class III or IV. At 30 days, procedural success was 94%, with no procedural deaths or conversions to surgery. A significant increase in QOL at 6 months follow-up was observed (baseline and 6-month Kansas City Cardiomyopathy Questionnaire scores 42.01 ± 22.3 and 59.7 ± 23.6, respectively; P = 0.004), correlating with a significant improvement in NYHA functional class, with 79.4% of patients noted to be in functional class I or II at 6 months (P = 0.0006). The rates of 6-month all-cause mortality and heart failure hospitalization were 8.5% and 20%, respectively. CONCLUSIONS: The dedicated bicaval system for treating severe symptomatic TR was associated with a high procedural success rate and significant improvements in both QOL and functional classification at 6 months follow-up.